Avian GCGR-mediated continuous fat utilization offers perspectives for obesity treatment
Human obesity is the fifth leading cause of global mortality. Fat mass loss and maintenance are central challenges for obesity management. In contrast, birds exhibit modest weight gain and limited fat accumulation due to rapid fat utilization as flight fuel. The physiology of this adaptation remained a mystery for a century. Here we show that cross-species single-nucleus RNA-sequencing analysis revealed high GCGR expression levels in avian adipocytes, while minimal in the adipose tissue of other vertebrates. Avian GCGR employs a unique rapid fat utilization mechanism for retaining a light body. Avian GCGR or other constitutively active GCGR variants (human GCGR<sup>H339R</sup>) expressed in white adipose tissue of male mice with obesity effectively promoted fat mobilization and sustained body weight loss, with decreased food intake partially contributing to the observed weight reduction. We suggest that avian GCGR plays this crucial role for fat utilization and may offer therapeutic potential for human obesity.
Authors
- Jiacheng Zhang (ORCID: https://orcid.org/0009-0003-6776-0370)
- Huaping Zheng (ORCID: https://orcid.org/0000-0002-0716-8987)
- Chenxi Feng (ORCID: https://orcid.org/0009-0005-4027-5580)
- Yiheng Jiang
- Wojciech Makałowski (ORCID: https://orcid.org/0000-0003-2303-9541)
- Cheng Deng (ORCID: https://orcid.org/0000-0002-5296-8879)
- Yang He (ORCID: https://orcid.org/0000-0002-9241-5101)
- Juergen Brosius (ORCID: https://orcid.org/0000-0003-1650-2059)
- Qiu Sun (ORCID: https://orcid.org/0000-0001-5122-2226)
- Yujun Shi (ORCID: https://orcid.org/0000-0003-0494-6023)
- Haidi Chen (ORCID: https://orcid.org/0000-0002-5105-5306)
- Xue Wang (ORCID: https://orcid.org/0009-0009-3062-2103)
- Xiaoou Li (ORCID: https://orcid.org/0000-0003-3087-7375)
- Qian Sun (ORCID: https://orcid.org/0000-0002-9532-3042)
- Peng Hu (ORCID: https://orcid.org/0000-0001-7029-1120)
- Song Leng (ORCID: https://orcid.org/0000-0001-6692-9195)
- Ting Zhang (ORCID: https://orcid.org/0000-0002-6679-0936)
- Shanshan Lai
- Chang Zhang (ORCID: https://orcid.org/0000-0002-5443-8951)
Institutions
- NSF NCAR High Altitude Observatory (US)
- Nanjing Normal University (CN)
- University of Münster (DE)
- Sichuan University (CN)
- West China Hospital of Sichuan University (CN)
- Shanghai Ocean University (CN)
- FH Münster University of Applied Sciences (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1038/s41467-025-66305-7
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Department of Science and Technology of Sichuan Province
- Sichuan University
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- National Science and Technology Major Project
- West China Hospital, Sichuan University